The generic particle formation technique referred to above comprises Solution Enhanced Dispersion by Supercritical fluids (SEDS technique) which is a technique for which the invention is particularly well-adapted. Various arrangements including nozzles that can be used are described in U.S. Pat. No. 5,851,453 (WO 9501221), U.S. Pat. No. 6,063,188 and US 2006073087 (WO 9600610), U.S. Pat. No. 6,440,337 (WO 9836825), WO 9944733, U.S. Pat. No. 6,576,262 (WO 9959710), U.S. Pat. No. 7,150,766 and U.S. Pat. No. 6,860,907 (WO 0103821), WO 0115664, US 2007116650 (WO 05061090) etc.
The SEDS techniques so far used have primarily worked for laboratory scale production. When scaling up to pilot plant scale there have been increasing problems with obtaining sufficiently small particles (mean size) and/or particles having a sufficiently narrow size distribution.
The solvents for the particle-forming substance have been aqueous or non-aqueous depending on the solubility characteristics and kind of substance to be transformed to a particulate state. For aqueous solvents the problem with size and size distribution have been more pronounced than for non-aqueous solvents due to a stronger tendency for the primarily formed particles to aggregate. For biologically active substances, such as most proteins, which require a specific three-dimensional structure for activity, and other biopolymers, aqueous solvents are normally preferred since non-aqueous solvents and/or organic solvents often are denaturing.
A typical spray nozzle has contained separate internal conduits for the solution and the fluid. These conduits have merged in a mixing arrangement upstream of or at the spray outlet of the nozzle. In a typical variant one of the conduits is placed inside the other conduit at least when approaching the spray outlet and/or the mixing arrangement, e.g. with the outer conduit cylindrical and coaxial with the inner conduit and a merging angle between the two conduits and between the two streams of essentially 0°. The nozzle has typically been placed in a chamber (particle collecting chamber) in which the formed particles have been separated and collected from the solvent and fluid used. The productivity of particles has been low. Upscaling has been difficult mainly due to the fact that particle size characteristics and/or morphology will change when increasing productivity by increasing nozzle parameters, such as flow velocities, internal conduit dimensions, concentration of particle-forming substance in the solution etc. The available intervals for mean sizes and size distributions of the particles have for many substances been unsatisfactory, in particular for particles that are intended for pharmaceutical uses. These problems have been most accentuated for batches in which the desired mean particle size is in the lowest part of the μm-range, e.g. ≦10 μm, such as ≦5 μm or ≦3 μm.
A promising solution to these problems is given by the spray nozzle presented in WO 2005061090. In this nozzle the stream of the super- or subcritical fluid is merging with the stream of the solution containing the substance at an angle β which is in the interval of 30°-150°. In the most important variants, the flow of one of the streams, e.g. the solution stream, at the point of merging is cylindrical with a direction coinciding with the direction of the axis of this cylindrical flow while the flow of the other stream is annular and directed radially outwards with a centre positioned on the axis of the cylindrical flow. See FIGS. 1-3 in WO 2005061090. It has been shown that the nozzle design presented in WO 2005061090 will facilitate increased productivity and improved control of morphology and particle mean size and size distribution. Thus it has been possible to lower mean sizes and preparing batches with narrower size distributions. In spite of the promising results obtained with this nozzle there is still a need for improvements facilitating still higher productivities and/or control of broader ranges of the size and morphology to cover a larger diversity of substances and their different uses.
Water-miscible organic solvents, such as ethanol, have been included as a modifier in the solution containing the particle-forming substance in order to facilitate extraction of water into the fluid thereby promoting nucleation and particle formation. See for instance U.S. Pat. No. 6,063,188 and US 2006073087 (WO 9600610). In other variants the supercritical fluid has contained the modifier:                U.S. Pat. No. 7,108,867 and US 2007009604 (WO 2002058674) describes a process in which the particle-forming substance is dissolved in water together with an agent having a solubility with a negative temperature dependency, and the supercritical fluid contains a liquid that is miscible both with water and the supercritical fluid. The process is performed at a temperature above the cloud point of the agent.        U.S. Pat. No. 6,461,642 (WO 0030613) describes a process in which water is included in the supercritical fluid before mixing with the solution containing the particle-forming substance.        
See also U.S. Pat. No. 5,851,453 (WO 9501221), and U.S. Pat. No. 6,063,188 and US 2006073087 (WO 9600610).
Supercritical fluids containing a solvent have also been used for modifying preformed particles. See U.S. Pat. No. 6,475,524 (WO 0030614).
Recycling of the supercritical fluid and/or performing a SEDS process in an arrangement comprising several particle collecting chambers has been suggested in WO 9501221 and WO 9600610. The chambers are suggested to be run in sequence with harvesting one chamber while another chamber is started, i.e. a kind of continuous process.